More than 60% of cancer patients receive radiation therapy (RT) during their anticancer treatment. However, there is a huge challenge to improve the therapeutic efficacy of RT in less radioresponsive tumors and decrease damages dealt to the surrounding healthy tissues. Herein, we have reported the development of an efficacious RT treatment of relatively radio-resistant breast cancer using W₁₈O₄₉ nanospheres and the second near-infrared (NIR) light irradiation. Featuring the X-ray attenuation ability and photothermal effect, together with ability to generate intracellular singlet oxygen and ·OH, W₁₈O₄₉ nanospheres can significantly increase radiation-induced DNA damage and decrease the mitochondrial membrane potential of cancer cells during RT, causing in nearby three-times improvement in inhibiting the proliferation of 4T1 cells. The in vivo evaluations verify that a rather effective therapeutic outcome is achieved by treatment of 4T1 tumor xenograft with NIR-enhanced RT using W₁₈O₄₉ nanospheres. Moreover, the X-ray attenuation ability and the strong near-infrared absorption of W₁₈O₄₉ nanospheres have enabled highly resolved in vivo computer tomography (CT)/photoacoustic (PA) imaging. This work presents an “all-in-one” synergistic platform to improve the therapeutic efficacy of RT in less radioresponsive tumors, therefore opening a new door for multimodal cancer therapy.